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1.
MMWR Morb Mortal Wkly Rep ; 69(2): 25-29, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31945037

RESUMO

Birth defects are a leading cause of infant mortality in the United States, accounting for 20.6% of infant deaths in 2017 (1). Rates of infant mortality attributable to birth defects (IMBD) have generally declined since the 1970s (1-3). U.S. linked birth/infant death data from 2003-2017 were used to assess trends in IMBD. Overall, rates declined 10% during 2003-2017, but decreases varied by maternal and infant characteristics. During 2003-2017, IMBD rates decreased 4% for infants of Hispanic mothers, 11% for infants of non-Hispanic black (black) mothers, and 12% for infants of non-Hispanic white (white) mothers. In 2017, these rates were highest among infants of black mothers (13.3 per 10,000 live births) and were lowest among infants of white mothers (9.9). During 2003-2017, IMBD rates for infants who were born extremely preterm (20-27 completed gestational weeks), full term (39-40 weeks), and late term/postterm (41-44 weeks) declined 20%-29%; rates for moderate (32-33 weeks) and late preterm (34-36 weeks) infants increased 17%. Continued tracking of IMBD rates can help identify areas where efforts to reduce IMBD are needed, such as among infants born to black and Hispanic mothers and those born moderate and late preterm (32-36 weeks).


Assuntos
Anormalidades Congênitas/mortalidade , Mortalidade Infantil/tendências , Afro-Americanos/estatística & dados numéricos , Anormalidades Congênitas/etnologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Disparidades nos Níveis de Saúde , Hispano-Americanos/estatística & dados numéricos , Humanos , Lactente , Mortalidade Infantil/etnologia , Lactente Extremamente Prematuro , Recém-Nascido , Criança Pós-Termo , Recém-Nascido Prematuro , Masculino , Estados Unidos/epidemiologia
2.
Occup Environ Med ; 77(3): 172-178, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31949041

RESUMO

OBJECTIVES: The aim of this study was to assess the association between maternal occupational exposure to solvents and gastroschisis in offspring. METHODS: We used data from the National Birth Defects Prevention Study, a large population-based case-control study of major birth defects conducted in 10 US states from 1997 to 2011. Infants with gastroschisis were ascertained by active birth defects surveillance systems. Control infants without major birth defects were selected from vital records or birth hospital records. Self-reported maternal occupational histories were collected by telephone interview. Industrial hygienists reviewed this information to estimate exposure to aromatic, chlorinated and petroleum-based solvents from 1 month before conception through the first trimester of pregnancy. Cumulative exposure to solvents was estimated for the same period accounting for estimated exposure intensity and frequency, job duration and hours worked per week. ORs and 95% CIs were estimated to assess the association between exposure to any solvents or solvent classes, and gastroschisis risk. RESULTS: Among 879 cases and 7817 controls, the overall prevalence of periconceptional solvent exposure was 7.3% and 7.4%, respectively. Exposure to any solvent versus no exposure to solvents was not associated with gastroschisis after adjusting for maternal age (OR 1.00, 95% CI 0.75 to 1.32), nor was an association noted for solvent classes. There was no exposure-response relationship between estimated cumulative solvent exposure and gastroschisis after adjusting for maternal age. CONCLUSION: Our study found no association between maternal occupational solvent exposure and gastroschisis in offspring. Further research is needed to understand risk factors for gastroschisis.

3.
Nat Commun ; 10(1): 4558, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594949

RESUMO

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

4.
Nat Commun ; 10(1): 4267, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537805

RESUMO

Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.


Assuntos
Doenças Cardiovasculares/genética , Metilação de DNA/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Idoso , Ilhas de CpG/genética , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
5.
Mol Psychiatry ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31501510

RESUMO

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

6.
Birth Defects Res ; 111(20): 1618-1632, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31328417

RESUMO

BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens. METHODS: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA. RESULTS: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol. CONCLUSIONS: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers.

7.
Sci Rep ; 9(1): 7523, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101869

RESUMO

Genetic studies of psychiatric disorders often deal with phenotypes that are not directly measurable. Instead, researchers rely on multivariate symptom data from questionnaires and surveys like the PTSD Symptom Scale (PSS) and Beck Depression Inventory (BDI) to indirectly assess a latent phenotype of interest. Researchers subsequently collapse such multivariate questionnaire data into a univariate outcome to represent a surrogate for the latent phenotype. However, when a causal variant is only associated with a subset of collapsed symptoms, the effect will be challenging to detect using the univariate outcome. We describe a more powerful strategy for genetic association testing in this situation that jointly analyzes the original multivariate symptom data collectively using a statistical framework that compares similarity in multivariate symptom-scale data from questionnaires to similarity in common genetic variants across a gene. We use simulated data to demonstrate this strategy provides substantially increased power over standard approaches that collapse questionnaire data into a single surrogate outcome. We also illustrate our approach using GWAS data from the Grady Trauma Project and identify genes associated with BDI not identified using standard univariate techniques. The approach is computationally efficient, scales to genome-wide studies, and is applicable to correlated symptom data of arbitrary dimension.

8.
BMJ Open ; 9(3): e026297, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30928950

RESUMO

OBJECTIVE: To assess the association between occurrence and timing of maternal self-reported genitourinary tract infection (urinary tract infections [UTIs] and/or sexually transmitted infection [STI]) and risk for gastroschisis in the offspring. DESIGN: Population-based case-control study. SETTING: National Birth Defects Prevention Study, a multisite study in the USA. PARTICIPANTS: Mothers of 1366 gastroschisis cases and 11 238 healthy controls. MAIN OUTCOME MEASURES: Crude and adjusted ORs (aORs) with 95% CIs. RESULTS: Genitourinary infections were frequent in case (19.3%) and control women (9.9%) during the periconceptional period (defined as 3 months prior to 3 months after conception). UTI and/or STI in the periconceptional period were associated with similarly increased risks for gastroschisis (aOR 1.5, 95% CI 1.3 to 1.8; aOR 1.6, 95% CI 1.2 to 2.3, respectively). The risk was increased with a UTI before (aOR 2.5; 95% CI 1.4 to 4.5) or after (aOR 1.7; 95% CI 1.1 to 2.6) conception only among women ≥25 years of age. The risk was highest among women <20 years of age with an STI before conception (aOR 3.6; 95% CI 1.5 to 8.4) and in women ≥25 years of age, the risk was similar for before (aOR 2.9; 95% CI 1.0 to 8.5) and after (aOR 2.8; 95% CI 1.3 to 6.1) conception. A specific STI pathogen was reported in 89.3% (50/56) of cases and 84.3% (162/191) of controls with Chlamydia trachomatis the most common (25/50 cases, 50%; 58/162 controls, 36%) and highest among women <20 years of age (16/25 cases, 64%; 22/33 controls, 67%). CONCLUSIONS: UTI and/or STI were associated with an increased risk for gastroschisis, with the strength of the association varying by maternal age and timing of infection.

9.
Addict Biol ; 23(5): 1145-1159, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29082582

RESUMO

Excessive alcohol use is extremely prevalent in the United States, particularly among trauma-exposed individuals. While several studies have examined genetic influences on alcohol use and related problems, this has not been studied in the context of trauma-exposed populations. We report results from a genome-wide association study of alcohol consumption and associated problems as measured by the alcohol use disorders identification test (AUDIT) in a trauma-exposed cohort. Results indicate a genome-wide significant association between total AUDIT score and rs1433375 [N = 1036, P = 2.61 × 10-8 (dominant model), P = 7.76 × 10-8 (additive model)], an intergenic single-nucleotide polymorphism located 323 kb upstream of the sodium channel and clathrin linker 1 (SCLT1) at 4q28. rs1433375 was also significant in a meta-analysis of two similar, but independent, cohorts (N = 1394, P = 0.0004), the Marine Resiliency Study and Systems Biology PTSD Biomarkers Consortium. Functional analysis indicated that rs1433375 was associated with SCLT1 gene expression and cortical-cerebellar functional connectivity measured via resting state functional magnetic resonance imaging. Together, findings suggest a role for sodium channel regulation and cerebellar functioning in alcohol use behavior. Identifying mechanisms underlying risk for problematic alcohol use in trauma-exposed populations is critical for future treatment and prevention efforts.


Assuntos
Alcoolismo/complicações , Alcoolismo/genética , Estudo de Associação Genômica Ampla/métodos , Canais de Sódio/genética , Transtornos de Estresse Pós-Traumáticos/complicações , Adolescente , Adulto , Afro-Americanos/estatística & dados numéricos , Idoso , Alcoolismo/fisiopatologia , Encéfalo/fisiopatologia , Estudos de Coortes , Feminino , Georgia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
10.
Genet Epidemiol ; 42(2): 156-167, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29285792

RESUMO

Many large GWAS consortia are expanding to simultaneously examine the joint role of DNA methylation in addition to genotype in the same subjects. However, integrating information from both data types is challenging. In this paper, we propose a composite kernel machine regression model to test the joint epigenetic and genetic effect. Our approach works at the gene level, which allows for a common unit of analysis across different data types. The model compares the pairwise similarities in the phenotype to the pairwise similarities in the genotype and methylation values; and high correspondence is suggestive of association. A composite kernel is constructed to measure the similarities in the genotype and methylation values between pairs of samples. We demonstrate through simulations and real data applications that the proposed approach can correctly control type I error, and is more robust and powerful than using only the genotype or methylation data in detecting trait-associated genes. We applied our method to investigate the genetic and epigenetic regulation of gene expression in response to stressful life events using data that are collected from the Grady Trauma Project. Within the kernel machine testing framework, our methods allow for heterogeneity in effect sizes, nonlinear, and interactive effects, as well as rapid P-value computation.


Assuntos
Metilação de DNA , Epigênese Genética , Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Interação Gene-Ambiente , Genótipo , Humanos , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Análise de Regressão , Projetos de Pesquisa , Estresse Psicológico/genética
11.
Genome Med ; 9(1): 99, 2017 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-29178946

RESUMO

BACKGROUND: The nature and underlying mechanisms of the observed increased vulnerability to posttraumatic stress disorder (PTSD) in women are unclear. METHODS: We investigated the genetic overlap of PTSD with anthropometric traits and reproductive behaviors and functions in women. The analysis was conducted using female-specific summary statistics from large genome-wide association studies (GWAS) and a cohort of 3577 European American women (966 PTSD cases and 2611 trauma-exposed controls). We applied a high-resolution polygenic score approach and Mendelian randomization analysis to investigate genetic correlations and causal relationships. RESULTS: We observed an inverse association of PTSD with genetically determined anthropometric traits related to body shape, independent of body mass index (BMI). The top association was related to BMI-adjusted waist circumference (WCadj; R = -0.079, P < 0.001, Q = 0.011). We estimated a relative decrease of 64.6% (95% confidence interval = 27.5-82.7) in the risk of PTSD per 1-SD increase in WCadj. MR-Egger regression intercept analysis showed no evidence of pleiotropic effects in this association (Ppleiotropy = 0.979). We also observed associations of genetically determined WCadj with age at first sexual intercourse and number of sexual partners (P = 0.013 and P < 0.001, respectively). CONCLUSIONS: There is a putative causal relationship between genetically determined female body shape and PTSD, which could be mediated by evolutionary mechanisms involved in human sexual behaviors.


Assuntos
Pesos e Medidas Corporais , Transtornos de Estresse Pós-Traumáticos/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reprodução , Risco , Comportamento Sexual
12.
MMWR Morb Mortal Wkly Rep ; 66(3): 84-87, 2017 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-28125575

RESUMO

Birth defects are a leading cause of infant mortality in the United States (1), accounting for approximately 20% of infant deaths. The rate of infant mortality attributable to birth defects (IMBD) in the United States in 2014 was 11.9 per 10,000 live births (1). Rates of IMBD differ by race/ethnicity (2), age group at death (2), and gestational age at birth (3). Insurance type is associated with survival among infants with congenital heart defects (CHD) (4). In 2003, a checkbox indicating principal payment source for delivery was added to the U.S. standard birth certificate (5). To assess IMBD by payment source for delivery, CDC analyzed linked U.S. birth/infant death data for 2011-2013 from states that adopted the 2003 revision of the birth certificate. The results indicated that IMBD rates for preterm (<37 weeks of gestation) and term (≥37 weeks) infants whose deliveries were covered by Medicaid were higher during the neonatal (<28 days) and postneonatal (≥28 days to <1 year) periods compared with infants whose deliveries were covered by private insurance. Similar differences in postneonatal mortality were observed for the three most common categories of birth defects listed as a cause of death: central nervous system (CNS) defects, CHD, and chromosomal abnormalities. Strategies to ensure quality of care and access to care might reduce the difference between deliveries covered by Medicaid and those covered by private insurance.


Assuntos
Anormalidades Congênitas/mortalidade , Parto Obstétrico/economia , Mortalidade Infantil , Seguro Saúde/estatística & dados numéricos , Adulto , Anormalidades Congênitas/etnologia , Feminino , Idade Gestacional , Humanos , Lactente , Mortalidade Infantil/etnologia , Recém-Nascido , Medicaid/estatística & dados numéricos , Gravidez , Setor Privado/estatística & dados numéricos , Estados Unidos/epidemiologia , Adulto Jovem
13.
Brain Behav Immun ; 61: 176-183, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27884623

RESUMO

Toxoplasma gondii (TOXO) is a neuroinvasive protozoan parasite that induces the formation of persistent cysts in mammalian brains. It infects approximately 1.1million people in the United States annually. Latent TOXO infection is implicated in the etiology of psychiatric disorders, especially schizophrenia (SCZ), and has been correlated with modestly impaired cognition. The acoustic startle response (ASR) is a reflex seen in all mammals. It is mediated by a simple subcortical circuit, and provides an indicator of neural function. We previously reported the association of TOXO with slowed acoustic startle latency, an index of neural processing speed, in a sample of schizophrenia and healthy control subjects. The alterations in neurobiology with TOXO latent infection may not be specific to schizophrenia. Therefore we examined TOXO in relation to acoustic startle in an urban, predominately African American, population with mixed psychiatric diagnoses, and healthy controls. Physiological and diagnostic data along with blood samples were collected from 364 outpatients treated at an inner-city hospital. TOXO status was determined with an ELISA assay for TOXO-specific IgG. A discrete titer was calculated based on standard cut-points as an indicator of seropositivity, and the TOXO-specific IgG concentration served as serointensity. A series of linear regression models were used to assess the association of TOXO seropositivity and serointensity with ASR magnitude and latency in models adjusting for demographics and psychiatric diagnoses (PTSD, major depression, schizophrenia, psychosis, substance abuse). ASR magnitude was 11.5% higher in TOXO seropositive subjects compared to seronegative individuals (p=0.01). This effect was more pronounced in models with TOXO serointensity that adjusted for sociodemographic covariates (F=7.41, p=0.0068; F=10.05, p=0.0017), and remained significant when psychiatric diagnoses were stepped into the models. TOXO showed no association with startle latency (t=0.49, p=0.63) in an unadjusted model, nor was TOXO associated with latency in models that included demographic factors. After stepping in individual psychiatric disorders, we found a significant association of latency with a diagnosis of PTSD (F=5.15, p=0.024), but no other psychiatric diagnoses, such that subjects with PTSD had longer startle latency. The mechanism by which TOXO infection is associated with high startle magnitude is not known, but possible mechanisms include TOXO cyst burden in the brain, parasite recrudescence, or molecular mimicry of a host epitope by TOXO. Future studies will focus on the neurobiology underlying the effects of latent TOXO infection as a potential inroad to the development of novel treatment targets for psychiatric disease.


Assuntos
Reflexo de Sobressalto/imunologia , Meio Social , Toxoplasma/imunologia , Toxoplasmose/imunologia , População Urbana , Estimulação Acústica , Adulto , Afro-Americanos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Genet Epidemiol ; 40(8): 722-731, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27488097

RESUMO

Kernel machine learning methods, such as the SNP-set kernel association test (SKAT), have been widely used to test associations between traits and genetic polymorphisms. In contrast to traditional single-SNP analysis methods, these methods are designed to examine the joint effect of a set of related SNPs (such as a group of SNPs within a gene or a pathway) and are able to identify sets of SNPs that are associated with the trait of interest. However, as with many multi-SNP testing approaches, kernel machine testing can draw conclusion only at the SNP-set level, and does not directly inform on which one(s) of the identified SNP set is actually driving the associations. A recently proposed procedure, KerNel Iterative Feature Extraction (KNIFE), provides a general framework for incorporating variable selection into kernel machine methods. In this article, we focus on quantitative traits and relatively common SNPs, and adapt the KNIFE procedure to genetic association studies and propose an approach to identify driver SNPs after the application of SKAT to gene set analysis. Our approach accommodates several kernels that are widely used in SNP analysis, such as the linear kernel and the Identity by State (IBS) kernel. The proposed approach provides practically useful utilities to prioritize SNPs, and fills the gap between SNP set analysis and biological functional studies. Both simulation studies and real data application are used to demonstrate the proposed approach.


Assuntos
Peso ao Nascer/genética , Interpretação Estatística de Dados , Estudos de Associação Genética , Marcadores Genéticos/genética , Polimorfismo de Nucleotídeo Único/genética , Seleção Genética/genética , Ferimentos e Lesões/genética , Endotelina-1/genética , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Modelos Genéticos , Fenótipo
15.
Depress Anxiety ; 33(4): 265-80, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27038408

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene-environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide by environment interaction study (GWEIS) of depressive symptoms. METHODS: Using data from the SHARe cohort of the Women's Health Initiative, comprising African Americans (n = 7,179) and Hispanics/Latinas (n = 3,138), we examined genetic main effects and GxE with stressful life events and social support. We also conducted a heritability analysis using genome-wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts. RESULTS: No SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20 kb from GPR139, P = 5.75 × 10(-8) ) and rs75407252 (intronic to CACNA2D3, P = 6.99 × 10(-7) ). In Hispanics/Latinas, the top signals were rs2532087 (located 27 kb from CD38, P = 2.44 × 10(-7) ) and rs4542757 (intronic to DCC, P = 7.31 × 10(-7) ). In the GEWIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; P = 4.10 × 10(-10) ; located 14 kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG = 0.95), suggesting that common variation underlying self-reported depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample. CONCLUSIONS: Our results underscore the need for larger samples, more GEWIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities.


Assuntos
Afro-Americanos/genética , Depressão/genética , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Hispano-Americanos/genética , Afro-Americanos/psicologia , Afro-Americanos/estatística & dados numéricos , Idoso , Depressão/psicologia , Feminino , Hispano-Americanos/psicologia , Hispano-Americanos/estatística & dados numéricos , Humanos , Acontecimentos que Mudam a Vida , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Autorrelato
17.
Child Dev ; 87(1): 122-34, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26822448

RESUMO

Childhood abuse can alter biological systems and increase risk for adult psychopathology. Epigenetic mechanisms, alterations in DNA structure that regulate the gene expression, are a potential mechanism underlying this risk. While abuse associates with methylation of certain genes, particularly those in the stress response system, no study to date has evaluated abuse and methylation of the oxytocin receptor (OXTR). However, studies support a role for OXTR in the link between abuse and adverse adult outcomes, showing that abuse can confer greater risk for psychiatric symptoms in those with specific OXTR genotypes. This study therefore sought to (a) assess the role of epigenetics in the link between abuse and psychopathology and (b) begin to integrate the genetic and epigenetic literature by exploring associations between OXTR genotypes and DNA CpG methylation. Data on 18 OXTR CpG sites, 44 single nucleotide polymorphisms, childhood abuse, and adult depression and anxiety symptoms were assessed in 393 African American adults (age = 41 ± 12.8 years). Overall, 68% of genotypes were associated with methylation of nearby CpG sites, with a subset surviving multiple test correction. Child abuse associated with higher methylation of two CpG sites yet did not survive correction or serve as a mediator of psychopathology. However, abuse interacted with CpG methylation to predict psychopathology. These findings suggest a role for OXTR in understanding the influence of early environments on adult psychiatric symptoms.


Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis , Afro-Americanos/psicologia , Ansiedade/etiologia , Metilação de DNA/genética , Depressão/etiologia , Epigênese Genética/genética , Receptores de Ocitocina/genética , Adolescente , Adulto , Afro-Americanos/genética , Idoso , Ansiedade/genética , Ilhas de CpG , Depressão/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
18.
Nat Commun ; 6: 10106, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26632874

RESUMO

DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3' un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.


Assuntos
RNA Helicases DEAD-box/metabolismo , Depressão/enzimologia , MicroRNAs/metabolismo , Ribonuclease III/metabolismo , Transtornos de Estresse Pós-Traumáticos/enzimologia , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/metabolismo , Estudos de Coortes , RNA Helicases DEAD-box/genética , Depressão/diagnóstico por imagem , Depressão/genética , Depressão/metabolismo , Depressão/psicologia , Regulação para Baixo , Medo , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Radiografia , Ribonuclease III/genética , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/psicologia
19.
Am J Med Genet B Neuropsychiatr Genet ; 168B(5): 327-36, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25988933

RESUMO

Genetic factors appear to be highly relevant to predicting differential risk for the development of post-traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome-wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N = 147) that was designed as a case-controlled sample of highly exposed, recently returning veterans with and without combat-related PTSD. A genome-wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N = 147, ß = 31.34, P = 1.28 × 10(-8) ) was found to associate with the gold-standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow-up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N = 2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N = 2006, P = 0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N = 157, P = 0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N = 53, P < 0.05) in the GTP replication sample. These data identify a genome-wide significant polymorphism conferring risk for PTSD, which was associated with differential epigenetic regulation and with differential cortical responses to fear in a replication sample. These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder.


Assuntos
Epigênese Genética/genética , Face/fisiologia , Medo , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Metilação de DNA , Expressão Facial , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Locos de Características Quantitativas/genética , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/psicologia , Veteranos/psicologia
20.
Am J Respir Crit Care Med ; 192(1): 47-56, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25918834

RESUMO

RATIONALE: Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR). OBJECTIVES: To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma. METHODS: This was a cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms, and maternal stress using the Perceived Stress Scale. Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke, and use of inhaled corticosteroids. MEASUREMENTS AND MAIN RESULTS: High child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, Checklist of Children's Distress Symptoms) and whose mothers had high stress (upper quartile, Perceived Stress Scale) had a BDR that was 10.2% (95% confidence interval, 6.1-14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This single-nucleotide polymorphism is associated with reduced expression of the gene for the ß2-adrenergic receptor (ADRB2) in CD4(+) lymphocytes of subjects with asthma, and it affects brain connectivity of the amygdala and the insula (a biomarker of anxiety). CONCLUSIONS: High child stress and an ADCYAP1R1 single-nucleotide polymorphism are associated with reduced BDR in children with asthma. This is likely caused by down-regulation of ADRB2 in highly stressed children.


Assuntos
Ansiedade/complicações , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Estresse Psicológico/complicações , Adolescente , Ansiedade/diagnóstico , Ansiedade/etnologia , Ansiedade/genética , Asma/complicações , Asma/etnologia , Asma/genética , Estudos de Casos e Controles , Criança , Estudos Transversais , Regulação para Baixo , Feminino , Marcadores Genéticos , Genótipo , Humanos , Modelos Lineares , Masculino , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Porto Rico , Receptores Adrenérgicos beta 2/genética , Rhode Island , Fatores de Risco , Estresse Psicológico/diagnóstico , Estresse Psicológico/etnologia , Resultado do Tratamento
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